Summary of Work: There is concern for the carcinogenic potential of carbonyl sulfide by inhalation because it is chemically reactive and is expected to react with tissues of the respiratory tract. Furthermore, carbonyl sulfide is the oxidation product of carbon disulfide which has been shown to be positive in the strain A mouse lung tumor bioassay. Significant increases in the incidence of lung tumors were observed in A/J mice. NTP found that carbonyl sulfide produced a weak positive response in the Ames assay (these are the only genetic toxicity data). Genotoxicity and cancer research issues will be evaluated in the p53 knock out mouse and TG.AC mouse, followed by chronic testing in rats and mice. For noncancer toxicities, there is a neurotoxic concern for carbonyl sulfide. An acute toxicity study in rats via inhalation for 4 hours showed some central nervous system effects at 1,062 and 1,189 ppm. An inhalation study in rabbits at 54 ppm for 7 weeks also reported neurological disorders. However, these studies are not sufficient to adequately characterize the neurological risk of carbonyl sulfide because they were not intended to provide a full evaluation of appropriate parameters for neurotoxicity following both acute and subchronic exposures. The approach to the study is to conduct an integrated inhalation toxicity study in-house including toxicokinetic, neurological, behavioral, electrophysiological and pathological end points examining dose response relationships and potential mechanisms of toxicity. Information from these studies will then be used to plan longer term studies and examine potential mechanisms of toxicity. A third concern is that a two generation study is needed to assess the effects on lactation and the reproductive performance of the second generation that was exposed during development. A short term reproductive and developmental toxicity screen will be used to provide data as to whether reproductive and developmental effects occur following COS exposure.